PROJECT SUMMARY Both African Americans living in segregated socioeconomically disadvantaged urban neighborhoods and resource-poor residents of rural areas experience high rates of premature mortality and a disproportionate burden of cardiovascular disease, cancer, and other adverse health conditions. Explaining how varied experiences of material and social disadvantage become embodied and subsequently manifest in racial and geographic health disparities is the key challenge for research, policy, and practice. While persistent social disadvantage is known to shape health disparities, the biological mechanisms that underlie this process ? known as weathering ? remain to be elucidated. The recent discovery of differential rates of biological aging (measured using DNA methylation) across subpopulations facing early life disadvantage suggest that the epigenome may play a key role in weathering. Epigenetic markers have also been linked with known disparities in multiple chronic conditions. The Researching Epigenetics, Weathering, Aging & Residential Disadvantage (REWARD) study will advance our understanding of DNA methylation as one epigenetic mechanism linking social, economic, and geographic disadvantage with accelerated aging and phenotypes of inflammation and cardio-metabolic diseases. Our goal is to determine how different dimensions of disadvantage ? including individual characteristics (e.g. racial identification, socioeconomic status, and associated experiences of discrimination), and neighborhood-level contextual characteristics (e.g. concentrated poverty, racial segregation, and rural isolation) ? shape health disparities through epigenetic mechanisms. We hypothesize that early-life and cumulative personal and contextual disadvantage predict DNA methylation patterns, creating biological signatures of weathering that contribute to accelerated biological aging, inflammation, and cardiometabolic disease in vulnerable populations. Few studies possess the temporal range of follow-up, geographic diversity, and extremes in racial segregation and rural isolation needed to test the hypothesis that individual and neighborhood-level disadvantage across the life course contribute to biological signatures of adversity. REWARD fills these gaps using rich data from an ongoing population based cohort in Wisconsin -- a state known for stark disparities including urban racial segregation and rural isolation. Using the 850K Infinium EPIC Chip array, we will analyze whole blood DNA and serum from 1400 participants in the Survey of the Health of Wisconsin (SHOW), an ongoing, well-characterized, population-based cohort of Wisconsin adults. The diverse team includes scientists from the University of Wisconsin-Madison?s School of Medicine and Public Health and Department of Sociology, as well as a leading biological anthropologist from Northwestern University and the UCLA-based geneticist and biostatistician who developed the Horvath epigenetic clock. The REWARD Study?s unique combination of genetic, socio-demographic, behavioral, and neighborhood-level data will allow our multidisciplinary research team to provide new insights by (Aim 1) examining differences in DNA methylation signatures across multiple domains of disadvantage; (Aim 2) investigating the epigenetic mechanisms linking accelerated biological aging with functional gene expression, inflammation, and cardio-metabolic disease; and (Aim 3) characterizing the impact of disadvantage across the life course on longitudinal changes in epigenetic markers of aging and disease. Findings from this research will highlight the variability in human biological response to adversity and inform interventions to prevent and treat age-related disease, reduce and mitigate health disparities, and improve the health of aging populations.